Stephen J. O'Brien

Bio: Stephen J. O'Brien is an academic researcher from Saint Petersburg State University of Information Technologies, Mechanics and Optics. The author has contributed to research in topics: Population & Gene. The author has an hindex of 153, co-authored 1062 publications receiving 93025 citations. Previous affiliations of Stephen J. O'Brien include University College Cork & QIMR Berghofer Medical Research Institute.

Revision anterior cruciate ligament reconstruction: etiology of failures and clinical results.

Abstract: A retrospective study was performed to determine the etiology of failed primary anterior cruciate ligament (ACL) reconstruction and evaluate the clinical results of revision ACL surgery. From January 1989 to January 1996, 90 patients with failed ACL reconstructions underwent revision ACL surgery. The etiology of failed ACL reconstruction included 47 surgical technical errors, 22 traumatic reinjuries, 7 lack of graft incorporation, 3 loss of motion, 3 related to synthetic grafts, and 8 alignment or combined ligamentous instability patterns not addressed. Of 52 revision ACL patients with minimum 2-year follow-up, 43 responded to a questionnaire and underwent a comprehensive physical examination. The Hospital for Special Surgery knee ligament evaluation revealed 63% good/excellent results. Objective laxity test revealed 77% of all patients had 0/+1 grade on Lachman and a mean 2.86-mm KT 1000. The overall results of revision ACL surgery are encouraging in providing symptomatic relief and restoring stability; however, they are significantly lower than primary ACL surgery.

Outcome in patients with nonleukemic granulocytic sarcoma treated with chemotherapy with or without radiotherapy

Abstract: Granulocytic sarcoma (GS) is an extramedullary tumor composed of immature myeloid cells The objectives of this study were to describe the frequency, presenting characteristics, and survival in patients with nonleukemic GS by conducting a review of all untreated patients presenting to the MD Anderson Cancer Center between January 1990 and June 2002 In all, 21 patients with nonleukemic GS, 1520 patients with acute myeloid leukemia (AML), and 402 patients with high-risk myelodysplastic syndrome (MDS) were identified GS occurred in 14% of patients with AML, and 11% of patients with AML or high-risk MDSs The median patient age was 57 years (range, 7-81) Among 20 patients with available cytogenetics in tissue and/or bone marrow, six had chromosome 8 abnormalities The median follow-up of surviving patients is 12 months (range, 7-75) In all, 20 patients were treated Patients were treated with AML-type chemotherapy (n=16), chemotherapy and radiotherapy (n=3), or radiotherapy alone (n=1) A total of 13 patients (65%) achieved complete remission and one patient (5%) achieved partial remission The median overall survival was 20 months (range, 1-75), median overall failure-free survival was 12 months (range, 1-75) The median survival of patients with chromosome 8 abnormalities was 12 months compared with 40 months of those without (P=017) Novel therapies for patients with GS are required

Exclusive and Persistent Use of the Entry Coreceptor CXCR4 by Human Immunodeficiency Virus Type 1 from a Subject Homozygous for CCR5 Δ32

Abstract: Cellular entry of human immunodeficiency virus type 1 (HIV-1) requires binding both to CD4 (14, 33, 40) and to one of the seven transmembrane G-protein-coupled chemokine receptors recently discovered to act as coreceptors (2, 6, 8, 11, 16, 19, 20, 24, 46). Viruses able to infect cultured T-cell lines (T tropic) are syncytium inducing (SI), are frequently found in late-stage HIV disease, and utilize the chemokine receptor CXCR4; macrophage-tropic (M-tropic) viruses are non-SI (NSI) in T-cell lines, are found throughout disease, and utilize CCR5 (2, 6, 8, 11, 16, 19, 20, 24, 46). Two other chemokine receptors, CCR2B and CCR3, function as minor HIV-1 entry coreceptors (11, 19, 48), with CCR3 likely playing a role in central nervous system HIV-1 infection (27). Recently, two seven-transmembrane receptors with extensive sequence homology to CCR5 and CXCR4—Bonzo (3, 17) and BOB (17, 22)—have been shown to mediate entry of simian immunodeficiency virus (SIV), as well as some M-tropic HIV-1 and HIV-2 strains. Another seven-transmembrane receptor, GPR1, mediates the entry of SIV but not HIV-1 (22). The CC chemokines RANTES, MIP-1α, and MIP-1β are natural ligands for CCR5 (49, 51), and the CXC chemokine stromal-cell-derived factor 1 (SDF-1) is the only known natural ligand for CXCR4 (8, 46, 49, 51). Ligand binding to both receptors is associated with G-protein-coupled signal transduction and leukocyte chemoattraction (8, 46, 49, 51), as well as partial viral-entry antagonism (2, 8, 11–13, 16, 20, 29, 46, 58). Viral entry and signal transduction are separable in vitro functions for CCR5 (4, 23, 26), but the two may be biologically related to viral pathogenesis in vivo. Most viral isolates recovered during primary and early chronic infection are NSI regardless of the route of infection (56, 59). Evolution of coreceptor use from CCR5 to CXCR4 is coincident with viral phenotypic switch from NSI to SI and progression to AIDS in approximately half of all HIV-1-seropositive subjects (31, 32, 34, 43, 54). A 32-bp inactivating deletion in CCR5 (CCR5 Δ32) common to northern European populations (41) has been associated with delayed disease progression in heterozygotes (15, 18, 21, 28, 43, 50, 60) and especially in those harboring NSI virus (18, 43). Subjects homozygous for CCR5 Δ32 (CCR5 −/−) are at a sharply reduced risk for virus transmission (15, 21, 28, 38, 43, 52, 60). However, reports of HIV-1 infected CCR5 −/− individuals, by our group and others, demonstrate that this risk reduction is finite (5, 7, 47, 55). We now report the viral phenotype, replication kinetics, macrophage tropism, and coreceptor usage of viruses derived early and late in disease from an HIV-1-infected CCR5 −/− subject.

Viruses of the Serengeti: Patterns of infection and mortality in African lions

Abstract: Summary 1. We present data on the temporal dynamics of six viruses that infect lions (Panthera leo) in the Serengeti National Park and Ngorongoro Crater, Tanzania. These populations have been studied continuously for the past 30 years, and previous research has documented their seroprevalence for feline herpesvirus, feline immunodeficiency virus (FIV), feline calicivirus, feline parvovirus, feline coronavirus and canine distemper virus (CDV). A seventh virus, feline leukaemia virus (FeLV), was absent from these animals. 2. Comprehensive analysis reveals that feline herpesvirus and FIV were consistently prevalent at high levels, indicating that they were endemic in the host populations. Feline calici-, parvo- and coronavirus, and CDV repeatedly showed a pattern of seroprevalence that was indicative of discrete disease epidemics: a brief period of high exposure for each virus was followed by declining seroprevalence. 3. The timing of viral invasion suggests that different epidemic viruses are associated with different minimum threshold densities of susceptible hosts. Furthermore, the proportion of susceptibles that became infected during disease outbreaks was positively correlated with the number of susceptible hosts at the beginning of each outbreak. 4. Examination of the relationship between disease outbreaks and host fitness suggest that these viruses do not affect birth and death rates in lions, with the exception of the 1994 outbreak of canine distemper virus. Although the endemic viruses (FHV and FIV) were too prevalent to measure precise health effects, there was no evidence that FIV infection reduced host longevity.

HLA-Cw*04 and Hepatitis C Virus Persistence

Abstract: In studies of acute hepatitis C virus (HCV) infection, the early host immune response is one of the determinants of viral persistence. The class I human leukocyte antigens (HLA), which present foreign antigen to cytolytic T cells, are integral components of this response. We hypothesized that the highly polymorphic HLA genes affect the outcome of an HCV infection. To test this hypothesis, we molecularly typed 231 persons with well-documented clearance of an HCV infection and 444 matched persistently infected persons. HLA-A*1101 (odds ratio [OR], 0.49; 95% confidence interval [95% CI], 0.27 to 0.89), HLA-B*57 (OR, 0.62; 95% CI, 0.39 to 1.00), and HLA-Cw*0102 (OR, 0.43; 95% CI, 0.21 to 0.89) were associated with viral clearance, whereas HLA-A*2301 (OR, 1.78; 95% CI, 1.01 to 3.11) and HLA-Cw*04 (OR, 1.78; 95% CI, 1.21 to 2.59) were associated with viral persistence. HLA-Cw*04 is in strong linkage disequilibrium with HLA-B*53 and HLA-B*35 , but only HLA-B*53 (OR, 1.70; 95% CI, 0.95 to 3.06) and the Cw*04-B*53 haplotype (OR, 1.76; 95% CI, 0.94 to 3.26) were weakly associated with viral persistence. HLA-B*53 has similar, but not necessarily identical, binding specificity to some HLA-B*35 subtypes ( B*35-Px group). The association with the B*35-Px group was less strong than with HLA-B*53 alone. The association of HLA-Cw*04 with HCV persistence was codominant (two copies of the gene were more strongly associated with persistence than one copy). However, HLA-Cw*04 was not associated with HCV RNA levels among the persistently infected individuals. Since Cw*04 is a ligand for the killer immunoglobulin-like receptors on natural killer cells, these cells may be involved in recovery from HCV infection. Further investigation is needed to understand the relationship between class I alleles and HCV clearance.

Initial sequencing and analysis of the human genome.

Abstract: The human genome holds an extraordinary trove of information about human development, physiology, medicine and evolution. Here we report the results of an international collaboration to produce and make freely available a draft sequence of the human genome. We also present an initial analysis of the data, describing some of the insights that can be gleaned from the sequence.

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

Abstract: 抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls

Abstract: There is increasing evidence that genome-wide association ( GWA) studies represent a powerful approach to the identification of genes involved in common human diseases. We describe a joint GWA study ( using the Affymetrix GeneChip 500K Mapping Array Set) undertaken in the British population, which has examined similar to 2,000 individuals for each of 7 major diseases and a shared set of similar to 3,000 controls. Case-control comparisons identified 24 independent association signals at P < 5 X 10(-7): 1 in bipolar disorder, 1 in coronary artery disease, 9 in Crohn's disease, 3 in rheumatoid arthritis, 7 in type 1 diabetes and 3 in type 2 diabetes. On the basis of prior findings and replication studies thus-far completed, almost all of these signals reflect genuine susceptibility effects. We observed association at many previously identified loci, and found compelling evidence that some loci confer risk for more than one of the diseases studied. Across all diseases, we identified a large number of further signals ( including 58 loci with single-point P values between 10(-5) and 5 X 10(-7)) likely to yield additional susceptibility loci. The importance of appropriately large samples was confirmed by the modest effect sizes observed at most loci identified. This study thus represents a thorough validation of the GWA approach. It has also demonstrated that careful use of a shared control group represents a safe and effective approach to GWA analyses of multiple disease phenotypes; has generated a genome-wide genotype database for future studies of common diseases in the British population; and shown that, provided individuals with non-European ancestry are excluded, the extent of population stratification in the British population is generally modest. Our findings offer new avenues for exploring the pathophysiology of these important disorders. We anticipate that our data, results and software, which will be widely available to other investigators, will provide a powerful resource for human genetics research.